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Abstract

Background

Respiratory irritants represent a major cause of occupational obstructive airway diseases.
We provide an overview of the evidence related to irritative agents causing occupational
asthma or occupational COPD.

Methods

We searched MEDLINE via PubMed. Reference lists of relevant reviews were also screened.
The SIGN grading system was used to rate the quality of each study. The modified RCGP
three-star system was used to grade the body of evidence for each irritant agent regarding
its causative role in either occupational asthma or occupational COPD.

Results

A total of 474 relevant papers were identified, covering 188 individual agents, professions
or work-sites. The focus of most of the studies and the predominant diagnosis was
occupational asthma, whereas occupational COPD arose only incidentally.

Conclusion

This study let us assume that irritant-induced occupational asthma and especially
occupational COPD are considerably underreported. Defining the evidence of the many
additional occupational irritants for causing airway disorders will be the subject
of continued studies with implications for diagnostics and preventive measures.

Occupational asthma is defined as a chronic inflammatory disorder of the airways with
recurrent episodes of coughing, wheezing, chest tightness, dyspnea, shortness of breath
at rest, and reversible airflow limitations caused by a particular occupational environment
[1-3].

The available epidemiological and comparative studies and reviews provide evidence
that occupational agents cause 5 – 25% of all asthma cases
[1,4-23]. Besides these evident occupational asthma (OA) cases, there is probably an even
larger population of sufferers of work-aggravated asthma
[24-26]. The latter population shows an objective worsening of pre-existing asthma or non-occupational
asthma that develops in parallel with causative conditions encountered in the workplace
(Figure
1).

Many case reports, case series and a few cross-sectional studies demonstrate that
a single short-term accidental massive exposure or several short-term high-level exposures
to a respiratory irritant can cause asthma within 24 hours without a latency period.
Brooks et al.
[30] defined this disorder as “reactive airways dysfunction syndrome” (RADS). This term
was later extended to irritant-induced OA from multiple, somewhat lower, exposure
incidents with a less sudden onset that were also shown to cause this disorder
[27,31-36].

Furthermore, there is evidence that a susceptible subgroup of subjects mainly atopics
with non-specific bronchial hyperresponsiveness (NSBHR) suffering from irritant-induced
OA, is also affected by chronic exposures to relatively low concentrations of irritant
gases, fumes or aerosols
[27,37,38]. This disorder has been called “low-dose irritant asthma” (or “low-dose RADS”). Corresponding
studies indicate respiratory effects including asthma from mainly chronic or repeated
exposure to a single irritant or a mixture. Demonstrably causative concentrations
of a particular irritant are often below their occupational exposure limits (OELs)
or permissible exposure limits (PELs). Such irritant examples include swine confinement
facilities
[39,40], exposures to cleaning agents
[12,41], solvents, ozone, endotoxin, formaldehyde, quaternary ammonium compounds, chlorine,
bisulfite and SO2, or acid mist
[36,37,42-44], diesel exhaust
[10,45,46], fumigant residues
[47], dusts in the textile paper, mineral fiber or construction industries or in mines
[48-51], as well as a proportion of cases of potroom asthma
[52] and meatwrappers' asthma
[53]. Asthma in cold-air athletes may also be relevant
[54,55]. A previous summary of the literature on respiratory effects from asthma due to irritants
below their OELs/PELs is available
[56]. Many of the earlier exposure limits have been lowered repeatedly in the light of
subsequent clinical or epidemiological findings on their respiratory effects. Other
limits remain obstinately high given their known irritative effects and/or that they
are based on sparse data
[56]. Accordingly, adherence to OELs/PELs does not preclude the onset of WRA in susceptible
subjects.

The broader definition of these disorders (as used in the legal definition in Germany)
includes all irritant-induced obstructive airway diseases irrespective of their causative
concentrations and reversibility, i.e. irritant-induced occupational asthma as well
as COPD.

Frequency of OA

OA has become the most prevalent occupational lung disease in developed countries
[57,58] and it is one of the most frequent diagnosis among occupational diseases in general
[59]. The annual incidence of OA is in the range of 50 per million with extremes up to
250 per million workers and more than 1,300 per million in specific workplaces
[57,60]. As already mentioned there is evidence that occupational agents cause 5 - 25% of
of all asthma cases. However, complete registries of OA do not exist and therefore
the true frequency of the disease is unknown. Ameille et al.
[61] and Fernández-Nieto et al.
[59] stated that OA is underestimated among occupational diseases, because many OA cases
are not subjected to appropriate diagnostic tests.

Irritant-induced OA is reported to occur in approximately 5 -18% of all OA cases,
being the second most common form of OA after allergic OA
[36,62].

The diagnosis of COPD is based on chronic productive cough, airflow limitation that
is usually not fully reversible, and a progressive, abnormal inflammative response
of the lungs mostly caused by long-term smoking and by other noxious particles or
gases
[1].

During ongoing causative exposures (e.g. smoking particles, droplets and/or gases),
airflow limitation is usually progressive and associated with an abnormal inflammatory
response of the lungs. Patients with COPD have greater number of neutrophils and alveolar
macrophages in bronchoalveolar lavage fluid than healthy non-smokers
[63]. Sites of emphysema, which are frequently found in COPD patients, contain large numbers
of lymphocytes, and the extent of lymphocyte accumulation correlates with reduction
of FEV1.

In their summaries of the literature, Hnizdo et al.
[64], Trupin et al.
[65] and Balmes et al.
[1] found an occupational contribution in about 15% of COPD cases.

At later stages of OA, the condition of some subjects does not improve over weekends
or during holidays and coincides with symptoms of COPD patients. This observation
also applies to non-occupational obstructive airways diseases
[69,70] and indicates that a group with changing diagnoses as well as with some overlap between
OA and occupational COPD, does exist
[66,71-73].

Background and objective

WRA and occupational COPD are serious and sometimes fatal diseases, which can lead
to ill health, inability to work and lost productivity
[1,25,74-76]. They represent a huge economic burden to the society. For details see Additional
file
1: Online Supplement “Economic burden”.

The objective of this study is to summarize present knowledge on respiratory irritants
causing obstructive airway diseases in humans in the occupational setting and to provide
a rating of the strength of evidence for each irritant which has not been previously
available.

Methodology

A systematic review of the literature on occupational irritant-induced OA and occupational
COPD due to occupational irritants was conducted. We considered asthma-inducing irritating
agents as well as those reported to cause occupational COPD and related disorders,
where obstructive ventilation patterns were demonstrated in clinical investigations,
cross-sectional studies, cross-shift and/or in long-term exposure studies. Irritating
gases mainly occurring in the general environment, such as ozone, and inorganic dusts,
including silica, talcum, silicates and other fibers known to cause pneumoconioses,
were not considered even though exposure to them is frequently associated with mixed
ventilation patterns.

Definitions used

Occupational COPD: chronic bronchitis symptoms and non-reversible airflow limitation
due to particular occupational environment (if lung function data was available; otherwise,
clinical diagnosis as given by the authors is cited).

Occupational asthma: episodes of shorteness of breath due to particular occupational
environment and reversible airflow limitation (if lung function data was available;
otherwise, clinical diagnosis as given by the authors is cited).

Information sources and selection criteria

Occupational respiratory irritants

To identify the evidence of irritants of the respiratory tract, all agents denoted
as “may cause respiratory irritation” by the phrase H335 (previous code R37) and “may
cause allergy or asthma symptoms or breathing difficulties if inhaled” H334 (previous
code R42)
[78] and/or as “irritants” by American Conference of Governmental Industrial Hygienists
[79] were initially listed
[80]; later this list was compared with results of our database search (see below).

Database search.

We searched for publications reporting investigations exclusively in humans (i.e.
animal or in-vitro research was excluded). To be included, the publications had to
deal with subjects occupationally exposed to airway irritants.

MEDLINE®-Database was searched with PubMed® from its inception up to December 2007
with the following medical subject headings (MeSH) combinations for each single agent:

Conditions

Four different conditions were accepted for inclusion:

1. Irritant-induced OA including RADS. Asthma caused by single or multiple occupational
exposures to airway irritants; de novo irritant-induced OA. Asthma within 24 hours
without a latency period caused by short-term high-level exposures to a respiratory
irritant known as acute irritant-induced asthma, or as RADS
[30].

Methodological selection criteria

Publications with one of the following study designs were included: Systematic reviews
of cohorts, case–control or cross-sectional studies, cohort studies (prospective/retrospective),
case–control studies, cross-sectional studies, surveys.

Non-analytic1a studies (i.e. case series, follow-up of cases or case reports) were only included
when for an agent no studies with one of the above mentioned designs had been identified.

Publications were included when they met any of the following criteria: examining
the frequency of irritant-induced OA or asthmatic work-related symptoms in occupationally
exposed groups or individuals, reporting the causative role of the specific agent
or mixture of agents for irritant-inducing WRA or COPD.

Studies were included when they applied any of the following diagnostic tools: description
of work-related asthmatic symptoms (questionnaire), lung function test (LFT), testing
for non-specific bronchial hyperresponsiveness (NSBHR) by means of methacholine, histamine
or other pharmacological agents, serial spirometry or expiratory peak flow (PEF) monitoring
or supervised exposure testing in the workplace, challenge with the help of lung function
measurements (SFT), specific inhalation challenge testing (SIC), clinical diagnosis
of OA by an expert (occupational or pulmonary physician), and exposure to an irritant
agent.

Publication period: No restriction for publication dates were made, last updates were
between 5th and 15th June 2012.

Language: English, German, Spanish, Italian or French.

Methodological studies, e.g. on effects of study design and subsequent procedures,
and studies with non-occupational disorders were excluded. Publications about occupational
agents which do not have an irritant effect on the respiratory tract (e.g. about IgE-sensitizing
agents) or with unrelated issues (e.g. studies on immunological questions) were also
excluded.

Assessment of study quality

Additional file 2.“Methodology” Selection criteria, information sources, strength of evidence. Table A: Data extraction and synthesis. Table B. Quality assessment of individual
study. Table C - The revised Scottish Intercollegiate Guidelines Network (SIGN) grading
system (modifications are given in italics)
[87]. Table D The Royal College of General Practitioners (RCGP) three-star system
[88] used by the British Occupational Health Research Foundation
[3,574] (modifications are given in italics).

We assessed study quality with the help of a check list (see Additional file
2: Table S1B of online supplement “Methodology”). The evidence level of each study
was graded according to the revised Scottish Intercollegiate Guidelines Network (SIGN)
grading system
[87]. Since population-based randomized assignment to different levels of irritant exposure
are unethical, no randomised controlled trials (RCTs) could be expected on this topic
and, thus, no level 1 evidence (as defined by the revised SIGN grading system)
[87] would be available. In order to achieve more differentiation among lower evidence
grades, we modified the SIGN grading system and added an additional grade (3+) (see
Additional file
2: Table S1C of online supplement “Methodology”).

Details of the modified RCGP
[88] grading system are given in the online supplement “Methodology”, Additional file
2: Table S1D.

Exclusively self-reported asthma symptoms or physician reported asthma as documented
in questionnaires as an alternative diagnosis for OA was used in 36 studies.

Other studies (n = 44) had not clear diagnosis of OA or occupational COPD but reported
obstructive ventilation pattern. The number of subjects with asthma symptoms and frequencies
of obstructive ventilation patterns and/or NSBHR are provided for each study (see
Additional file
3: Table S2E of online supplement “Results”).

Occupational COPD as outcome

As already mentioned, occupational COPD was not specifically addressed in most of
the studies. Some describe respiratory symptoms, such as chronic bronchitis (n = 21),
which may be indicative of COPD. One of the few studies which specifically focused
on COPD, was a large retrospective cohort study on diesel exhaust which caused a significantly
increased COPD mortality in railroad workers after the introduction of diesel engines
in 1945
[105,106]. Construction work was identified as a cause of occupational COPD in 2 publications
[8,107].

Evidence level of the literature

Some publications investigated more than one irritant agent and thus have been considered
several times in our study.

262 of the 474 publications were non-analytic studies and were rated according to
SIGN as 4, 3 or 3+ and consisted of case reports (n = 228), case series (n = 63),
and occupational diseases statistics (n = 33) and reviews of that kind of studies
(n = 7). The other publications reported analytical studies and were rated according
to SIGN as 2+ (n = 15), 2- (n = 103), or 3+ (n = 83).

The highest level was 2+, indicating a well conducted analytical study (case control
or cohort studies) with a low risk of confounding or bias (n = 15 studies). Other
studies with a similar design had a higher risk of confounding or bias and were individually
rated lower by SIGN grading of 2- (n = 30 studies). Most of the other analytical studies
were rated with a SIGN grade of 2-, because their design (cross-sectional or longitudinal
study) was limiting (n = 82 studies). Cross-sectional studies or longitudinal studies,
e.g. those with high risk of confounding or bias, were rated even lower with 3/ 3+
(n = 35 studies). A couple of study designs were difficult to classify epidemiologically,
including those which were surveys, mostly with very low analytical evidence, rated
3/ 3+ (n = 53 studies), or larger surveys with a lower risk of confounding or bias,
which were graded with 2- (n = 4 studies).

Investigations involving dose–response relationship as a form of scientific evidence
were performed in 30 out of 474 studies analyzed
[68,105,106,108-133].

Another assessment of the level of evidence found in individual studies is to consider
their OR for irritant-induced OA or occupational COPD; this was done in 39 publications
[15,23,44,48,105-108,113,117-120,122,126,128,134-156].

Strength of evidence per agent, work-site or profession

The outcome for each agent causing OA or occupational COPD was graded according to
the modified RCGP three-star system to classify the strength of evidence of its causative
role in irritant-induced OA/ occupational COPD. The strongest evidence achieved was
two stars “**” (indicating a moderate strength of evidence provided by generally consistent
findings in fewer, smaller or lower quality scientific studies) for 17 (mixed) agents,
work-sites or professions. For six of them (chlorine, platinum salts, environmental
tobacco smoke, welding fumes, construction work, World Trade Center disaster in 2001),
this level was based on well- conducted studies with low risk of confounding and/or
bias (SIGN 2+). For eleven of these 17 (mixed) agents, SIGN levels of individual studies
were lower (benzene-1, 2, 4-tricarboxylic acid-1,2-anhydride [trimellitic anhydride],
cobalt, isocyanates, cement dust, grain dust, animal farming (pig, beef/veal, dairy,
poultry), or swine confinement.

Limited or contradictory evidence – provided by only one analytical study or inconsistent
findings in multiple scientific studies, i.e.“*” – was identified for 39 agents, and
after down-grading because of inadequate methodological aspects, i.e. “[*]” on three
occasions. For the majority of agents, only non-analytical studies were reported for
≥ 5 cases, i.e. “(*)” or less than 5 cases, i.e. “-”. When only non-analytical studies
were available, the strength of evidence for the agent was raised if at least 5 cases
were identified by the case reports/ case series or occupational disease statistics
for which proof of irritant-induced OA or occupational COPD existed. The strength
of evidence reached when only non-analytical studies were available ranged from “very
limited or contradictory evidence” in 29 studies, i.e. “(*)”, to “no scientific evidence”
“-” 94 times. (see Tables
3 and
4 and Additional file
3: Table S2E of online supplement “Result”).

Table 4.Strength of evidence foragents, professions and work-siteaccording to the modifiedRCGP three-star system[88]

The compiled assessment of the individual studies, along with their relevant clinical
data and strength of evidence for irritant agents, professions or workplaces causing
asthma or COPD, is presented as a summary list (see Additional file
3: Table S2E “Results” for the full information).

Discussion

The main objective of this study was to give a comprehensive and evidence-based overview
of the literature on irritative agents, professions or work-sites causing irritant-induced
work-related asthma and occupational COPD. To our knowledge this study is the first
attempts to document these respiratory disorders, along with their causative irritant
agents in an evidence-based manner.

Strength and limitations

This work covers a broad range of causative agents of irritant-induced occupational
asthma or COPD. We included various study designs.

A strength of our work is that we not only assessed the quality of single investigations
but the strength of the body of evidence for each irritant agent.

The paradigm of “evidenced-based medicine” has been criticized by leading scientists
[547-550]. Bias in the selection of information may be a problem for generalization of findings
in single studies
[551,552]. In spite of these limitations, alternative approaches to evaluation of the literature
have not been generally accepted. Evaluation of the evidence depends on the domain,
which means the factors to be considered in assessing the extent to which the study
results are reliable or valid.

Kunz et al.
[553] stressed the approach of grading scientific studies on basis of additional qualified
data, i.e. dose response relationships. This latter was seen in 30/474 individual
studies in this current work. Other studies were based on evidence by OR >2 or < 0.5
for irritant-induced OA and occupational COPD which was applied as an approach in
40/474 individual studies (see Additional file
3: Table S2E of online supplement “Results”).

There are numerous procedural methods for rating the strength of scientific evidence.
The AHRQ emphasized in 2002: “systems for grading the strength of a body of evidence
are much less uniform than those for rating study quality”
[554].

It is possible that not all relevant studies were found in our search of literature.
Probably, some studies could not be found by the MeSH term raster applied. Relying
solely on MeSH terms might be a problem in the identification of studies of irritant-induced
OA or occupational COPD. We restricted the search to the MeSH fields in order to increase
the specificity of the search. As for any electronic search strategy, an increase
of specificity implies a decrease in sensitivity of the search.

For each single study, we took into consideration possible risks due to confounding,
e.g. exposure to multiple agents and selection bias, e.g. healthy worker effect.

Basis and quality of data

Irritant-induced obstructive airways diseases cannot usually be diagnosed in one clinical
visit and, instead, follow-up and/or detailed clinical investigations are necessary.
The diagnostic “gold standard” for OA is SIC using a specific occupational agent in
an exposure chamber. SIC is particularly indicated in the clinical setting where new
causative substances with still unknown adverse respiratory sensitization potential
are suspected. This “gold standard” is not applicable for large studies; so, it was
used mainly in case series or reports.The evidence levels to confirm irritant-induced
work-relaated asthma or occupational COPD for the listed irritant agents, professions
or worksites (see Additional file
3: Table S2E of online supplement “Results”) are frequently low with the major reasons
being that high quality studies were missing and the quality of the available studies
was low. Nevertheless, this knowledge is the best available and may help physicians
to identify a suspected irritant agent as causative in irritant-induced work-related
asthma and / or occupational COPD
[555]. As also recently stressed by Quint et al.
[555], “implementing an evidence-based identification and regulatory process for OA will
help to ensure primary prevention of OA”. In cases of low evidence level of an agent
that does not exclude a causative role, caution should be exercised and a more detailed
diagnostic testing of relevant exposure should be performed.

Occupational COPD, an underestimated category

We identified only 20 out of 474 publications that referred to occupational COPD,
with most of them implicating inorganic or organic dust or fumes, such as cement dust,
construction work and diesel exhaust, as the causative agents.

As an example, the mixed agent cement dust was investigated in 14 studies but only
four studies documented cement dust as the causative agent in occupational COPD
[111,418,419,422] (see Table
3 and Additional file
3: Table S2E “Results”). The remaining 10 studies described irritant-induced OA cases
[235,423-426,530] or identified significant asthma symptoms/ obstructive ventilation patterns without
a clear diagnosis (5 studies:
[178,417,420,556]). It can be assumed that if it had been considered on the other 10 studies then occupational
COPD caused by cement dust would have been frequently observed.

The population-attributable fraction for COPD associated with occupational exposure
has been estimated between 9% and 31%
[1,64,65]. However the true population-attributable risk due to occupational exposure is unclear
[6,557] as occupational COPD is rarely clinically diagnosed. Blanc et al.
[558] recently published an ecological analysis using data from three large studies, comprising
the Burden of Obstructive Lung Disease study
[169], the Latin American Project for Investigation of Obstructive Lung Disease (PLATINO)
and the European Community Respiratory Health Survey follow-up (ECHRS II), where occupational
COPD was also not a primary goal. The original publications are mainly concerned with
OA or asthma symptoms, but a history of pre-existing OA or RADS cannot be allowed
to exclude occupational COPD
[559]. Blanc et al.
[558] stressed that the contribution of occupational exposure cannot be ignored, because
“the association between adverse working conditions and COPD (…) carries significance
as a global finding (…), alongside the (…) critical contribution of cigarette smoking
to disease prevalence”.

General acceptance of this statement does not exist
[66,559], although evidence for an association between individual exposure levels and COPD
is accumulating in the latest literature
[1,6,106,506,557,560,561].

Irritant-induced WRA – a broader definition

Irritant-induced OA includes three subcategories that predominantly differ according
to the concentration of irritants in the workplace atmosphere. It can occur without
a latency period, such as RADS, as was shown for 46 causative agents in our study,
with the highest prevalence after spills of acids or tear gas (see Additional file
3: Table S2E of online supplement“Results”). Other agents, e.g. isocyanates or welding
fumes, usually induce a slower onset of low dose irritant-induced asthma with a latency
period and mostly without evidence of an IgE-mediated pathomechanism.

The ACCP also stated in its last Consensus Statement in 2008
[24] that cases who do not meet the stringent criteria of RADS
[30] (e.g. where there is a lag of several days before the onset of symptoms or where
there is no single massive exposure but rather repeated exposure over days and weeks)
should be subsumed into a broader category of irritant-induced OA. As outlined in
the section “Introduction” Brooks et al.
[31] and later also others, e.g. Burge
[27] suggested using the term “not so sudden onset of irritant-induced asthma” for those
developing the disorder after such exposure within a period of 2 days to 4 months.
In an extended definition corresponding to ours, Burge
[27] he used the term “low dose irritant-induced OA” for those developing the disorder
after relatively low repeated exposure for more than 4 months.

Bardana
[562] and Vandenplas and Malo
[563] questioned whether such rather low concentrations could actually cause irritant-induced
OA. These different opinions about the pathogenetic role of chronic or recurrent exposure(s)
to low concentrations of respiratory irritants seem to be due to inadequate considering
of the increased susceptibility of a small group of workers. Occupational disease
statistics do mostly neither contain such cases nor work-aggravated asthma cases so
far.

Another critical issue is the frequent disregarding of work-aggravated asthma due
to occupational agents by physicians.

Comparison to occupational guidelines or consensus statements – what is new?

In the current analysis, the focus has been on irritant agents causing irritant-induced
occupational asthma and COPD. Both entities have been underestimated or even overlooked
in the past. Occupational COPD has not been considered as a subgroup of COPD thus
so far
[559,564]; and the definition of irritant-induced OA has been heterogenous at best
[24,552,565,566]. Furthermore, the guidelines dealing with respiratory disorders have not even considered
causation by individual irritant agents, so far.

The ACCP published a Consensus Statement in 2008
[24] which focuses on the diagnosis and management of WRA after a latency period, i.e.
due allergens and “sensitizers” with unknown pathomechanisms, effectively sidelining
irritant-induced OA to RADS.

The Agency for Healthcare Research and Quality (AHRQ) in its the Evidence Report “Diagnosis
and Management of WRA”
[552] addressed the key question of the best diagnostic approach for a patient with suspected
WRA. In respect of irritant-induced OA, they only considered RADS as a non-allergic
asthma due to mainly low molecular weight compounds of unknown pathomechanism.

The Canadian Thoracic Society “Guidelines for OA”
[567] was the first evidence-based guideline, although irritant-induced OA was limited
to RADS. If criteria were not fulfilled then irritant-induced OA was discussed as
a controversial diagnosis. The three evidence levels in the “Guidelines for OA” were
based on quality of scientific evidence within analyzed studies
[568]. Compared with the modified RCGP three-star grading (see Additional file
2: Table S2D in online supplement “Methodology”), the different levels are defined
in a more general way, i.e. not considering the quantitative aspect if only studies
with lower scientific evidence exist.

The evidence review and recommendations for OA by the BOHRF
[3,569] were designed to improve the prevention, identification and management of OA. This
work mainly deals with asthma after a latency period and considers irritant-induced
OA and RADS to be closely related entities. The difference in comparison with our
analysis is obvious even though our evidence-based approach was closely related to
the BOHRF guidelines and used the same grading systems.

In summary, the existing guidelines or statements mostly define irritant-induced OA
as RADS. Work-aggravated asthma, and occupational COPD as a distinct entity, have
not been considered in any guideline, although the latter is becoming recognized as
such in more recent publications
[557,559,564].

This evidence-based approach is the first which focuses on especially irritative agents
within the broader definition of irritant-induced OA and occupational COPD. For clarification,
the grading systems were modified in accordance with BOHRF
[3] when considering the extent and quality of the clinical investigations, with the
goal of creating evidence levels for causative irritative agents as precisely as possible.

Concluding remarks

OA is the most common chronic occupational lung disease in many industrialized countries
[3]. COPD is the fourth leading cause of death worldwide with a significant portion of
occupational cases
[66]. The term occupational COPD does not officially exist. However, it has to be considered
as a subcategory of COPD
[559].

Our study shows that reliable, sensitive and specific methods are required in the
diagnostic approach for confirming irritant-induced OA, work-aggravated asthma, or
occupational COPD. The specific diagnostic work-up in a subject with such a suspected
disorder depends on the individual clinical data and on the knowledge of asthma- or
COPD-inducing agents in the workplace. On this basis, our review may help in diagnostics
especially for agent exposures where we were able to relate irritant-induced work-related
asthma or occupational COPD to a high evidence-based level (i.e. two stars according
to the RCGP grading).

We have created a list representing the strength of evidence for irritating agents
to be causative in irritant-induced work-related asthma or occupational COPD (see
Additional file
3: Table S2E of online supplement “Results”).

A low level or absence of evidence for many agents in causing irritant-induced work-related
asthma or occupational COPD is sometimes due to contradictory findings in literature,
but is mostly due to the absence of rigorous scientific studies, with many gaps remaining
in the knowledge of a causative role for individual agents and conditions. Therefore,
and because of rarely applied diagnostic approach in the clinical setting, our literature
search and evaluation lead us to assume that irritant-induced respiratory disorders
are considerably underreported in cross-sectional studies and occupational disease
statistics.

Our list needs updating in the light of recent literature, in order to provide a realistic
overview of agents and evidence level in their causation of irritant-induced work-related
or occupational COPD.

The estimated high population-attributable risk in the range of 5–25% for occupational
asthma and COPD from occupational exposure, indicates that more detailed and intensive
research, as well as strategies designed to prevent these disorders, should receive
high priority in the global efforts to reduce the burden of these diseases. This implies
extended evidence-based diagnostic procedures that help to optimize primary and secondary
prevention by the physicians dealing with occupational diseases.

Reduction of the exposure to noxious agents by lowering the permissible exposure limits
is the best and favoured way for intervention. If this is not possible then other
effective primary preventive measures, such as wearing adequate respiratory devices,
are required
[28,570-574].

Finally, we would like to mention that the diagnosis of irritant-induced OA should
be considered if:

there has been exposure to high concentration of an irritative agent identified in
this study and the development of asthma without a latency period (original definition
of RADS) or

there has been chronic or repeated exposures to moderate (in the TLV ranges) concentrations
of an irritative agent identified in this review and the development of asthma with
a latency period, but without evidence of an IgE-mediated pathomechanism and

there is evidence that a highly susceptible subject (e.g. with pre-existing NSBHR)
develops new onset asthma upon occupational exposure to an identified irritative agent
even at concentrations below the TLV.

Work-aggravated asthma should be considered if:

there have been any of the before-mentioned exposures and

there is a temporally related significant worsening of a pre-existing asthma or of
a concomitant non-occupational asthma.

The diagnosis of occupational COPD should be considered if:

there has been exposure to an agent capable of causing occupational COPD, and

not reversible chronic airway disease is demonstrated and

there is a temporal relationship between the period of exposure (mostly cumulative
exposures to identified irritants ) and the development of COPD (acute WRA symptoms
are frequently missing).

Occupational COPD has to be taken into consideration especially in non-smokers, i.e.
when dominating non-occupational causes for COPD are obviously not present.

Endnotes

aEpidemiologic study design which is generally applied to test one or more specific
hypotheses, typically whether an exposure is a risk factor for a disease
[575].

Competing interests

The authors declare that they have no conflict of interest.

Authors' contributions

All authors made substantial contributions to the study. XB made the design of the
study and the final interpretation of data. HV and PB did the detailed literature
search, data extraction and analyses, and statistical analyses. XB and HV wrote the
manuscript with input from PB. All authors approved the final version for submission.

Acknowledgements

We thank Marcial Velasco Garrido for critical review and support in drafting the manuscript.

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European Parliament, The Council of EU: Regulation (EC) No 1272/2008 of the European Parliament and on the Council of 16 December
2008 on classification, labelling and packing of substances and mixtures, amending
and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulations (EC)
No 1907/2006.

Baur X: Occupational agents with respiratory effects according to ACGIH 2009 and / or classified
with the R42 phrase* (may cause sensitization by inhalation) and / or with the R37
phrase* (irritating to respiratory system) according to the European Union directives
67/548/EEC (1), 2001/59/EC (2), 2004/73/EC (3) or 2009/2/EC (4) (identical to ILO/CIS
2002.